1. Field of the Invention
The present invention relates to a process for manufacturing a highly purified, stable, non-hygroscopic, crystalline composition of L-DOPA ethyl ester. The L-DOPA ethyl ester (also known as LDEE) is an active ingredient in many pharmaceutical preparations for the treatment of patients suffering from Parkinson's disease and related indications.
2. Description of Related Art
Typically Parkinsonian patients are routinely treated with a combination of levodopa (L-DOPA) and a DOPA decarboxylase inhibitor such as carbidopa or benserazide. Unfortunately, after an initial period of satisfactory, smooth and stable clinical benefit from L-DOPA therapy lasting on the average 2-5 years, the condition of many patients deteriorates and they develop complex dose-related as well as unpredictable response fluctuations. The causes of the response fluctuations are probably multiple and complex, but pharmacokinetic problems (primarily faulty absorption of L-DOPA) may play a critical role. There is a correlation between the clinical fluctuations and the oscillations of L-DOPA plasma levels. Many of the problems are a result of the unfavorable pharmacokinetic properties of L-DOPA, i.e., very poor solubility, poor bio-availability and short half-life in vivo.
A more suitable L-DOPA ester for therapy would be the L-DOPA ethyl ester. However, it has been difficult to develop the L-DOPA ethyl ester in a form suitable for pharmaceutical use:
"In view of the potential toxicity that might arise from methanol formation the ethyl ester would ideally have been most suitable for assessment in humans. However, the ethyl ester could not be crystallized as its hydrochloride salt because of its hygroscopic potential. The methyl ester was therefore developed for use in humans." Stocci, F. et al, Movement Disorders, 7:249-256, (1992); at 254.
L-DOPA ethyl ester is described in the literature as the hydrochloride salt. However, it is difficult to isolate as a crystalline salt and therefore was described as an amorphous solid (Fix, et al., Pharm. Research 6(6):501-505 (1989)) which is not suitable for pharmaceutical use. Cooper, et al., Clinical Neuropharmacology 7:88-89 (1984) note that L-DOPA ethyl ester hydrochloride salt is hygroscopic and difficult to crystallize during synthesis. Clearly, a pure, stable, non-hygroscopic form of L-DOPA ethyl ester is needed for pharmaceutical purposes.
Salts and esters of L-DOPA, including the L-DOPA ethyl ester, are mentioned in Patent GB 1,342,286 for the treatment of alopecia. The only disclosure regarding the nature of the L-DOPA ethyl ester is that it can be prepared from L-DOPA by conventional methods. However, as noted above, preparation of L-DOPA ethyl ester by conventional methods yields a product which is not suitable for pharmaceutical use due to its impurity, its hygroscopicity, and its lack of stability.
Great Britain Patent No. 1,364,505 and corresponding U.S. Pat. No. 3,803,120, assigned to Hoffman-La Roche, describe the synthesis of L-DOPA ethyl ester hydrochloride salt and free base. This compound is used as an intermediate in the synthesis of other compounds and is not characterized in the patent specification. In agreement with the literature (Fix, et al., Pharm. Research 6(6):501-505 (1989); and Cooper, et al., Clin. Pharmacol. 7:88-89 (1984)) we have found that the L-DOPA ethyl ester hydrochloride salt synthesized by the methods described in these patents is hygroscopic, not stable, difficult to crystallize, and, as a result, difficult to purify. This material cannot be used for pharmaceutical compositions. Likewise, the L-DOPA ethyl ester free base as prepared in these two patents is impure and not stable and thus also is not suitable for pharmaceutical compositions. At best it can be used as a synthetic intermediate for further chemical synthesis as described in the cited patents.
Two references note the synthesis of racemic ethyl ester. (Ginssburg, et al., Zh. Obshch. Khim. 39:1168-1170 (1969) and Venter, et al., S. Afr. Tydskr. Chem. 31:135-137(1978)). Neither of these references prepare crystalline L-DOPA ethyl ester in a form suitable for pharmaceutical use and certainly there is no teaching or suggestion of the preparation of crystalline L-DOPA ethyl ester in a form suitable for pharmaceutical use. Both references prepare the material as an intermediate for the synthesis of other materials of interest.
More recently, Milman et al. (U.S. Pat. No. 5,354,885) described a new process for preparing pharmaceutically acceptable, crystalline, non-hygroscopic L-DOPA ethyl ester as free base. The Milman process provides L-DOPA ethyl ester of high purity, wherein at least 97% by weight is the L-DOPA ethyl ester while L-DOPA, as an impurity, is present in less than 1% by weight of the composition.
The crystalline, non-hygroscopic L-DOPA ethyl ester composition produced according to the Milman process is highly stable and remains as at least 97% by weight L-DOPA ethyl ester after incubation for 6 months at 40.degree. C. The availability of L-DOPA ethyl ester in such high purity made feasible the preparation of pharmaceutical compositions of L-DOPA ethyl ester, which compositions could not be successfully developed on a commercial scale until the development of the process.
The potential for increased demand of highly purified L-DOPA ethyl ester described in the U.S. Pat. No. 5,354,885, warrants research to find a simpler, more economical process for producing L-DOPA ethyl ester of high purity. While the Milman process produced a highly purified L-DOPA ethyl ester, the process is lengthy and complicated because it involves extraction steps.
The Milman process comprises reacting L-DOPA with ethanol in the presence of thionyl chloride or an acid catalyst to yield crude L-DOPA ethyl ester hydrochloride. Then volatiles are removed from the crude L-DOPA ethyl ester hydrochloride by vacuum distillation. The residue is then dissolved with water containing a suitable antioxidant and the pH is adjusted to between 6.0 and 7.0 using a suitable base to yield a solution containing L-DOPA ethyl ester free base. To obtain the free base in the solvent phase, the solution is extracted with a suitable solvent in the presence of a suitable antioxidant. The solvent phase is then concentrated at a temperature lower than 40.degree. C. to form a precipitate. The precipitate is then recrystallized in the presence of a second suitable solvent containing a second suitable antioxidant to yield the composition of pharmaceutically acceptable, crystalline, non-hygroscopic L-DOPA ethyl ester free base.
The present invention discloses an unexpectedly simpler process for manufacturing a composition comprising pharmaceutically acceptable, crystalline, non-hygroscopic L-DOPA ethyl ester as free base in an amount which is at least 95% by weight of the composition and L-DOPA in an amount which is less than 2% by weight of the composition.